Astrocyte-Derived Monocyte-Chemoattractant Protein-1 Directs the Transmigration of Leukocytes Across a Model of the Human Blood-Brain Barrier

• Published in: The Journal of immunology (1950) Vol. 161; no. 12; pp. 6896 - 6903
• Main Authors: Weiss, Jonathan M, Downie, Sherry A, Lyman, William D, Berman, Joan W
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.12.1998
• Subjects: Antibodies, Monoclonal - pharmacology; Antigens, CD - analysis; Antigens, Differentiation, T-Lymphocyte - analysis; Astrocytes - physiology; Blood-Brain Barrier; Cell Communication; Cells, Cultured; Chemokine CCL2 - antagonists & inhibitors; Chemokine CCL2 - immunology; Chemokine CCL2 - physiology; Chemotaxis, Leukocyte - drug effects; Coculture Techniques; E-Selectin - immunology; E-Selectin - physiology; Endothelium, Vascular - cytology; Flow Cytometry; Humans; Intercellular Adhesion Molecule-1 - immunology; Intercellular Adhesion Molecule-1 - physiology; Interferon-gamma - pharmacology; Interleukin-1 - pharmacology; Lectins, C-Type; Leukocytes, Mononuclear - cytology; Lymphocyte Activation; Recombinant Proteins; Transforming Growth Factor beta - pharmacology; Tumor Necrosis Factor-alpha - pharmacology; Umbilical Veins
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.161.12.6896

The migration of leukocytes across the blood-brain barrier (BBB) into the central nervous system is critical in the pathogenesis of central nervous system inflammatory diseases. The production of chemokines, such as monocyte-chemoattractant protein-1 (MCP-1), by endothelial cells (EC) and astrocytes may initiate and amplify this process. Using a coculture of human EC and astrocytes to model the BBB, we demonstrated that exogenous MCP-1 induces the transmigration of monocytes in a dose-dependent manner. TNF-alpha, IFN-gamma, or IL-1beta treatment of cocultures also induced significant migration of monocytes that correlates with the induction of MCP-1 protein. TGF-beta, previously shown to induce MCP-1 expression in astrocytes, but not in EC, caused migration of monocytes across cocultures, but not across EC grown alone. Monocytes and lymphocytes transmigrated across cytokine-treated cocultures in greater numbers than across EC alone. Astrocytes were the main source of cytokine-induced MCP-1, supporting a role for astrocytes in facilitating leukocyte transmigration. A blocking Ab to MCP-1 inhibited MCP-1- and cytokine-induced transmigration of monocytes by 85-90%. Cytokine treatment of cocultures also resulted in the transmigration of activated, CD69-positive lymphocytes. The MCP-1-mediated transmigration of monocytes across cocultures was blocked using an Ab to ICAM-1 and inhibited by 55% using an Ab to E-selectin. These data suggest a central role for astrocyte-derived MCP-1 in directing the migration of monocytes and lymphocytes across the BBB.